Crosslinkable polyisobutylene-based polymers and medical devices containing the same

ABSTRACT

The present invention pertains to crosslinkable and crosslinked polyisobutylene-based polymers, to compositions that contain such polymers, and to medical devices that are formed using such polymers. According to one aspect, the present invention pertains to crosslinkable and crosslinked compositions that comprise a copolymer that comprises a polyisobutylene segment and two or more reactive groups. According to another aspect, the present invention pertains to medical devices that contain such compositions. According to another aspect, the present invention pertains to methods of making medical devices using such compositions.

RELATED APPLICATIONS

This application claims priority from U.S. provisional application61/235,931, filed Aug. 21, 2009, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to crosslinkable polyisobutylene-basedpolymers and to medical devices containing the same.

BACKGROUND OF THE INVENTION

The use of polymeric materials in medical devices for implantation orinsertion into the body of a patient is common in the practice of modernmedicine. For example, polymeric materials such as silicone rubber,polyurethane, and fluoropolymers, for instance, polytetrafluoroethylene(PTFE), expanded PTFE (ePTFE) and ethylene tetrafluoroethylene (ETFE),are used as coating materials/insulation for medical leads, providingmechanical protection, electrical insulation, or both.

As another example, drug eluting stents are known which have polymericcoatings over the stent to release a drug to counteract the effects ofin-stent restenosis. Specific examples of drug eluting coronary stentsinclude commercially available stents from Boston Scientific Corp.(TAXUS, PROMUS), Johnson & Johnson (CYPHER), and others. See S. V.Ranade et al., Acta Biomater. 2005 January; 1(1): 137-44 and R. Virmaniet al., Circulation 2004 Feb. 17, 109(6) 701-5. Various types ofpolymeric materials have been used in such polymeric coatings including,for example, homopolymers such as poly(n-butyl methacrylate) andcopolymers such as poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropylene), and poly(isobutylene-co-styrene), forexample, poly(styrene-b-isobutylene-b-styrene) triblock copolymers(SIBS), which are described, for instance, in U.S. Pat. No. 6,545,097 toPinchuk et al. SIBS triblock copolymers have a soft, elastomeric lowglass transition temperature (Tg) midblock and hard elevated Tgendblocks. SIBS copolymers are thermoplastic elastomers and are highlybiocompatible.

SUMMARY OF THE INVENTION

The present invention pertains to crosslinkable and crosslinkedpolyisobutylene-based polymers, to compositions that contain suchpolymers, and to medical devices that are formed using such polymers.

According to one aspect, the present invention pertains to crosslinkableand crosslinked compositions that comprise a copolymer that comprises apolyisobutylene segment and two or more reactive groups.

According to another aspect, the present invention pertains to medicaldevices that contain such compositions.

According to another aspect, the present invention pertains to methodsof making medical devices using such compositions.

Among other benefits, crosslinking imparts improved abrasion resistance,decreased solubility and improved dimensional stability or resistance tocreep under load to the resulting compositions and devices. Benefitsassociated with the use of polyisobutylene-based polymers includebiostability and biocompatibility.

These and other aspects and embodiments as well as various additionaladvantages of the present invention will become readily apparent tothose of ordinary skill in the art upon review of the DetailedDescription and any Claims to follow.

DETAILED DESCRIPTION OF THE INVENTION

A more complete understanding of the present invention is available byreference to the following detailed description of numerous aspects andembodiments of the invention. The detailed description of the inventionwhich follows is intended to illustrate but not limit the invention.

According to one aspect, the invention pertains to compositionscomprising crosslinkable polyisobutylene homopolymers or copolymers(collectively referred to herein as “crosslinkable polyisobutylenepolymers”).

As is well known, “polymers” are molecules containing multiple copies(e.g., from 5 to 10 to 25 to 50 to 100 to 250 to 500 to 1000 or morecopies) of one or more constitutional units, commonly referred to asmonomers. As used herein, the term “monomers” may refer to free monomersand to those that have been incorporated into polymers, with thedistinction being clear from the context in which the term is used.

Polymers may take on a number of configurations, which may be selected,for example, from linear, cyclic and branched configurations, amongothers. Branched configurations include star-shaped configurations(e.g., configurations in which three or more chains emanate from asingle branch point), comb configurations (e.g., configurations having amain chain and a plurality of side chains, also referred to as “graft”configurations), dendritic configurations (e.g., arborescent and hyperbranched polymers), and so forth.

As used herein, “homopolymers” are polymers that contain multiple copiesof a single constitutional unit (i.e., monomer). “Copolymers” arepolymers that contain multiple copies of at least two dissimilarconstitutional units.

As used herein, a “polymer segment” or “segment” is a portion of apolymer. Polymer segments can be unbranched or branched. Polymersegments can contain a single type of constitutional unit (also referredto herein as “homopolymers segments”) or multiple types ofconstitutional units (also referred to herein as “copolymer segments”)which may be present, for example, in a random, statistical, gradient,or periodic (e.g., alternating) distribution.

As used herein a soft segment is one that displays a Tg that is belowbody temperature, more typically from 35° C. to 20° C. to 0° C. to −25°C. to −50° C. or below. A hard segment is one that displays a Tg that isabove body temperature, more typically from 40° C. to 50° C. to 75° C.to 100° C. or above. Tg can be measured by differential scanningcalorimetric (DSC), dynamic mechanical analysis (DMA) and thermomechanical analysis (TMA).

As noted above, in one aspect, the invention pertains to crosslinkablecompositions comprising crosslinkable polyisobutylene polymers.Polyisobutylene polymers may be rendered crosslinkable, for example, byproviding at least one reactive group within the polymer, for instance,at least one site of carbon-carbon unsaturation (e.g., corresponding to—CH═CH— or —C≡C—) within the polymer, and more typically two or moresites of carbon-carbon unsaturation (e.g., 2, 3, 4, 5, 10 or more),among other possibilities. As a general rule, the greater the number ofreactive groups (e.g., carbon-carbon unsaturation sites, etc.) in thepolymer, the greater the crosslinking density in the final product.

For example, in certain embodiments, polyisobutylene homopolymers of thefollowing formula (I) may be formed, which have terminal double bonds(i.e., vinyl groups):

where n is an integer of 2 or more (for example, ranging from 2 to 5 to10 to 25 to 50 to 100 to 250 to 500 to 1000 to 3,000, among othervalues). Polyisobutylene copolymers that comprise one or morepolyisobutylene segments, one or more non-polyisobutylene segments(several examples of which are described below), and terminal vinylgroups may also be formed for use in the present invention.

Although the preceding polyisobutylene polymers have terminal doublebonds, in other embodiments, polyisobutylene homopolymers and copolymershaving non-terminal double bonds are employed in the practice of theinvention. Examples include polymer of the following formula (II), whichhave internal double bonds:

where n is an integer of 2 or more (for example, ranging from 2 to 5 to10 to 25 to 50 to 100 to 250 to 500 to 1000 to 3,000, among othervalues); k is an integer of 1, 2, 3, 4, 5 or more, L is an initiatorresidue, R₁ is —CH₃, R₂ for each occurrence is independently —H, —X,—CH₂X, CHX₂, —CX₃, —C≡N or —NO₂, wherein X, for each occurrence, isindependently a halogen; Nu² is selected from —OH, —NH₂, halogen, —N₃,—O—CH₂C₂H, —OR₃ (wherein R₃ is a C1-C12 alkyl), a polymer or copolymersegment, thymine, —CH₂—C(O)OH, —C(O)N₃, —NHC(O)OR, —C(O)NHR, or—NHC(O)NHR, where R is a C1-C12 alkyl, or a peptide-NH— group. See,e.g., WO 2008/060333 to Faust. In certain embodiments, Nu²R₃ in formula(II) is a non-polyisobutylene polymer segment such as those describedbelow.

Polyisobutylene homopolymers and copolymers of the formula (II) may beused per se in the compositions of the invention, or they may be used toform further copolymers for use in the invention as discussed in moredetail below, for example, polyisobutylene urethane copolymers (e.g.,where Nu2 is —OH), polyisobutylene urea copolymers (e.g., where Nu2 is—NH2) or polyisobutylene urethane/urea copolymers (e.g., where Nu2 is—OH, —NH2, or a combination of both) may be formed. Urethane, urea andurethane/urea copolymers can also be formed using isocyanate terminatedpolyisobutylene (i.e., where Nu2 is replaced with —N═C═O).

Polyurethanes are a family of copolymers that are typically synthesizedfrom polyfunctional isocyanates (e.g., diisocyanates, including bothaliphatic and aromatic diisocyanates) and polyols (e.g., macroglycols).For example, polyurethanes in accordance with the invention may besynthesized from a macroglycol (e.g., a macrodiol) that contains one ormore polyisobutylene segments and one or more optionalnon-polyisobutylene segments. Aliphatic or aromatic diols and/ordiamines may also be employed as chain extenders, for example, to impartimproved physical properties to the polyurethane. For instance, hardness(Durometer) may be increased as a result of an increase the ratio ofhard segments (e.g., arising from aromatic diisocyantes such as MDI,etc.) to soft segments in the copolymer through the use of chainextenders. Where diamines are employed as chain extenders, urea linkagesare formed and the resulting polymers may be referred to aspolyurethane/polyureas.

Polyureas are a family of copolymers that are typically synthesized frompolyfunctional isocyanates and polyamines. For example, polyureas inaccordance with the invention may be synthesized from a diamine thatcontains one or more polyisobutylene segments and one or more optionalnon-polyisobutylene segments. As with polyurethanes, aliphatic oraromatic diols or diamines may be employed as chain extenders.

Note that analogous urethane, urea and urethane/urea copolymers can beformed by reversing the species upon which the isocyanates, alcohol andamine functionalities are provided, for example, using macromolecularpolyfunctional isocyanates to provide soft segments (e.g., apolyisobutylene-containing diisocyante, for instance, polymers of theformula (II) where Nu is —C≡N), small molecule diols or diamines toprovide hard segments (e.g., aromatic diols or diamines, for instance,methylenebisphenylene diol) and small molecule diisocyanates as chainextenders.

As noted above, urethane, urea and urethane/urea copolymers inaccordance with the invention typically comprise one or more one or moresites of unsaturation. For example, according to certain aspects of theinvention, polyisobutylene urethane, urea and urethane/urea copolymersare provided, which contain (a) one or more polyisobutylene segments,(b) one or more one or more sites of unsaturation (c) one or morediisocyanate residues, (d) one or more optional chain extender residuesand (e) one or more optional non-polyisobutylene polymer segments.

The one or more sites of unsaturation may be introduced into theurethane, urea and urethane/urea copolymers of the invention in variousways. For example, in certain embodiments of the invention, theunsaturated copolymers in accordance with the invention may be formedusing one or more of the following species: (a) macroglycols (e.g.,macrodiol) containing one or more sites of unsaturation (e.g., anunsaturated macroglycol containing one or more polyisobutylene segments,an unsaturated macroglycol containing one or more non-polyisobutylenepolymer segments, or an unsaturated macroglycol containing one or morepolyisobutylene segments and one or more non-polyisobutylene polymersegments), (b) diisocyanates containing one or more sites ofunsaturation and (c) chain extender residues containing one or more oneor more sites of unsaturation.

Examples of optional non-polyisobutylene segments include soft and hardpolymer segments such as polyether segments, fluoropolymer segmentsincluding fluorinated polyether segments, polyester segments,poly(acrylate) segments, poly(methacrylate) segments, polysiloxanesegments, polystyrene segments, and polycarbonate segments. As notedabove, in certain embodiments, such non-polyisobutylene segments areintroduced into the copolymers of the invention in the form ofmacroglycols (e.g., diols). Moreover, in certain embodiments, suchnon-polyisobutylene segments may be provided with one or more sites ofunsaturation.

Examples of polyether segments include linear, branched and cyclichomopoly(alkylene oxide) and copoly(alkylene oxide) segments, includinghomopolymers and copolymer segments formed from one or more of thefollowing, among others: methylene oxide, dimethylene oxide (ethyleneoxide), trimethylene oxide, propylene oxide, and tetramethylene oxide,pentamethylene oxide, and hexamethylene oxide and higher analogs.

In this regard, in some embodiments, a polyether diol compatibilizersuch as polytetramethylene oxide diol (PTMO diol) or polyhexametheyleneoxide diol (PHMO diol) may be added to a unsaturated polyisobutylenehomopolymers diol during synthesis process in order to promote uniformdistribution of the polyurethane hard segments into the PIB softsegments and to achieve favorable micro-phase separation in the polymer.Such polyalkylene oxides will also improve key mechanical propertiessuch as one or more of the following: tensile strength, tensile modulus,flexural modulus, elongation, tear strength, flex fatigue, tensilecreep, and abrasion performance, among others. The soft segmentcomposition in the reaction mixture can be varied by varying the weightratio of PIB diol to polyether diol (e.g., PTMO diol, PHMO diol, etc.)from, for example, 100:0, 99:1 to 95:5 to 90:10 to 75:25 to 50:50 to25:75 to 10:90 to 5:95 to 0.1:99.9, more preferably, from 90:10 to 85:15to 80:20 to 75:25 to 70:30. The PIB diol, polyether diol or both may beprovided with one or more sites of unsaturation in some embodiments.

Similarly, the weight ratio of soft segment (e.g., polyisobutylenesegment and non-polyisobutylene soft segment, if any) to hard segment(e.g., aromatic diisocyanate with chain extender, e.g. butanediol) inthe polyurethanes of the invention can be varied, for example, from 99:1to 95:5 to 90:10 to 75:25 to 50:50 to 25:75 to 10:90 to 5:95 to 1:99,more preferably, 95:5 to 90:10 to 80:20 to 70:30 to 65:35 to 60:40 to50:50, to achieve a variety of Shore hardness, a wide range of physicaland mechanical properties, and an array of functional performance.

Examples of soft fluoropolymer segments include perfluoroacrylatesegments and fluorinated polyether segments, for example, linear,branched and cyclic homopoly(fluorinated alkylene oxide) andcopoly(fluorinated alkylene oxide) segments, including homopolymeric andcopolymer segments formed from one or more of the following, amongothers: perfluoromethylene oxide, perfluorodimethylene oxide(perfluoroethylene oxide), perfluorotrimethylene oxide andperfluoropropylene oxide.

Examples of soft polyester segments include linear, branched and cyclichomopolymeric and copolymer segments formed from one or more of thefollowing, among others: alkyleneadipates including ethyleneadipate,propyleneadipate, tetramethyleneadipate, and hexamethyleneadipate.

Examples of soft poly(acrylate) segments include linear, branched andcyclic homopoly(acrylate) and copoly(acrylate) segments, includinghomopolymeric and copolymer segments formed from one or more of thefollowing, among others: alkyl acrylates such as methyl acrylate, ethylacrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, sec-butylacrylate, isobutyl acrylate, 2-ethylhexyl acrylate and dodecyl acrylate.

Examples of soft poly(methacrylate) segments include linear, branchedand cyclic homopoly(methacrylate) and copoly(methacrylate) segments,including homopolymeric and copolymer segments formed from one or moreof the following, among others: alkyl methacrylates such as hexylmethacrylate, 2-ethylhexyl methacrylate, octyl methacrylate, dodecylmethacrylate and octadecyl methacrylate.

Examples of soft polysiloxane segments include linear, branched andcyclic homopolysiloxane and copolysiloxane segments, includinghomopolymeric and copolymer segments formed from one or more of thefollowing, among others: dialkyl siloxanes such as dimethyl siloxane,diethyl siloxane, and methylethyl siloxane.

Examples of soft polycarbonate segments include those comprising one ormore types of carbonate units,

where R may be selected from linear, branched and cyclic alkyl groups.Specific examples include homopolymeric and copolymer segments formedfrom one or more of the following monomers, among others: ethylenecarbonate, propylene carbonate, and hexamethylene carbonate.

As indicated above, examples of optional non-polyisobutylene segmentsalso include hard polymer segments such as poly(vinyl aromatic)segments, poly(alkyl acrylate) and poly(alkyl methacrylate) segments.

Examples of hard poly(vinyl aromatic) segments include linear, branchedand cyclic homopoly(vinyl aromatic) and copoly(vinyl aromatic) segments,including homopolymeric and copolymer segments formed from one or moreof the following vinyl aromatic monomers, among others: styrene, 2-vinylnaphthalene, alpha-methyl styrene, p-methoxystyrene, p-acetoxystyrene,2-methylstyrene, 3-methylstyrene and 4-methylstyrene.

Examples of hard poly(alkyl acrylate) segments include linear, branchedand cyclic homopoly(alkyl acrylate) and copoly(alkyl acrylate) segments,including homopolymeric and copolymer segments formed from one or moreof the following acrylate monomers, among others: tert-butyl acrylate,hexyl acrylate and isobornyl acrylate.

Examples of hard poly(alkyl methacrylate) segments include linear,branched and cyclic homopoly(alkyl methacrylate) and copoly(alkylmethacrylate) segments, including homopolymeric and copolymer segmentsformed from one or more of the following alkyl methacrylate monomers,among others: methyl methacrylate, ethyl methacrylate, isopropylmethacrylate, isobutyl methacrylate, t-butyl methacrylate, andcyclohexyl methacrylate.

Examples of optional non-polyisobutylene segments further includebiodegradable linear, branched and cyclic homopolymeric and copolymersegments, for example, formed from one or more of the following, amongothers: d-lactic acid, l-lactic acid, glycolic acid, epsiloncaprolactone, and d,l-lactic acid, hydroxybutyrates, tyrosinepolyesters, tyrosine polycarbonates, polyesteramides, andpolyanhydrides.

The various polyisobutylene and optional non-polyisobutylene polymersegments described herein can vary widely in molecular weight, buttypically are composed of between 2 and 1000 repeat units (monomerunits), for example, ranging from 2 to 5 to 10 to 25 to 50 to 100 to 250to 500 to 1000 repeat units.

As noted above, the various polyisobutylene and optionalnon-polyisobutylene polymer segments described herein may be providedwith one or more reactive groups (e.g., one or more sites ofunsaturation) in some embodiments.

The various polyisobutylene and optional non-polyisobutylene polymersegments described herein can be incorporated into the polyurethanes,polyureas and polyurethane/polyureas of the invention by providing themin the form of polyols (e.g., diols, triols, etc.) or as polyamines(e.g., diamines, triamines, etc.). Although polyols are generallydescribed herein, it is to be understood that analogous methods may beperformed and analogous compositions may be created using polyamines andpolyol/polyamine combinations.

Specific examples of polyisobutylene polyols include linearpolyisobutylene diols and branched polyisobutylene polyols (e.g.,three-arm polyisobutylene triols) which may contain two or more sites ofunsaturation or which may be saturated (e.g., where unsaturation isintroduced via another entity). See, e.g., WO 2008/060333 to Faust, J.P. Kennedy et al., “Designed Polymers by Carbocationic MacromolecularEngineering: Theory and Practice,” Hanser Publishers 1991, pp. 191-193,Joseph P. Kennedy, Journal of Elastomers and Plastics 1985 17: 82-88,and the references cited therein. More specific examples include linearpolyisobutylene diols with a terminal —OH functional group at each endand with zero, one, two, three or more sites of unsaturation, which maybe formed, for example, using methods analogous to those described inthe preceding Faust and Kennedy references.

Specific examples of polyether polyols include polytetramethylene oxidediols, which are available from various sources including Signa-AldrichCo., Saint Louis, Mo., USA and E.I. duPont de Nemours and Co.,Wilmington, Del., USA. Specific examples of polysiloxane polyols includepolydimethylsiloxane diols, available from various sources including DowCorning Corp., Midland Mich., USA, Chisso Corp., Tokyo, Japan. Specificexamples of polycarbonate polyols include polyhexamethylene carbonatediols such as those available from Sigma-Aldrich Co. Specific examplesof polyfluoroalkylene oxide diols include ZDOLTX, Ausimont, Bussi,Italy, a copolyperfluoroalkylene oxide diol containing a randomdistribution of —CF2CF2O— and —CF2O— units, end-capped by ethoxylatedunits, i.e., H(OCH2CH2)nOCH2CF2O(CF2CF2O)p(CF2O)qCF2CH2O(CH2CH2O)nH,where n, p and q are integers. Polystyrene diol(α,ω-dihydroxy-terminated polystyrene) of varying molecular weight isavailable from Polymer Source, Inc., Montreal, Canada. Polystyrene diolsand three-arm triols may be formed, for example, using proceduresanalogous to those described in M. Weiβmüller et al., “Preparation andend-linking of hydroxyl-terminated polystyrene star macromolecules,”Macromolecular Chemistry and Physics 200(3), 1999, 541-551.

In some embodiments, polyols (e.g., diols, triols, etc.) are employedwhich are based on block copolymers. Specific examples of such blockcopolymer polyols include the following (which may contain zero, one,two or more sites of unsaturation): poly(tetramethyleneoxide-b-isobutylene) diol, poly(tetramethyleneoxide-b-isobutylene-b-alkylene oxide) diol, poly(dimethylsiloxane-b-isobutylene) diol, poly(dimethylsiloxane-b-isobutylene-b-dimethyl siloxane) diol, poly(hexamethylenecarbonate-b-isobutylene) diol, poly(hexamethylenecarbonate-b-isobutylene-b-hexamethylene carbonate) diol, poly(methylmethacrylate-b-isobutylene) diol, poly(methylmethacrylate-b-isobutylene-b-methyl methacrylate) diol,poly(styrene-b-isobutylene) diol andpoly(styrene-b-isobutylene-b-styrene) diol (SIBS diol).

Specific examples of homopolymeric and copolymeric polyisobutylenepolyols (and polyamines) which may be used in forming thepolyisobutylene urethane, urea and urethane/urea copolymers of theinvention include polymers of formula (II)

where n is an integer of or more 2 (for example, ranging from 2 to 5 to10 to 25 to 50 to 100 to 250 to 500 to 1000 to 3000, among othervalues); k is an integer of 1, 2, 3, 4, 5 or more, L is an initiatorresidue, R₁ is —CH₃, R₂ for each occasion is independently —H, —X,—CH₂X, CHX₂, —CX₃, —C≡N or —NO₂, wherein X, for each occurrence, isindependently a halogen (preferably R₂ is —H); and Nu² is selected from—OH, —NH₂, or —OR₃, wherein R₃ is a non-polyisobutylene segment such asthose described above with —OH or —NH₂ termination.

As noted above, polyisobutylene urethane, urea and urethane/ureacopolymers in accordance with the invention typically comprise one ormore diisocyanate residues and will also comprise one or more chainextender residues in many embodiments.

Diisocyanates for use in forming the urethane, urea and urethane/ureacopolymers of the invention include aromatic and non-aromatic (e.g.,aliphatic) diisocyanates. Aromatic diisocyanates may be selected fromsuitable members of the following, among others: 4,4′-methylenediphenyldiisocyanate (MDI), 2,4- and/or 2,6-toluene diisocyanate (TDI),1,5-naphthalene diisocyanate (NDI), para-phenylene diisocyanate,3,3′-tolidene-4,4′-diisocyanate and3,3′-dimethyl-diphenylmethane-4,4′-diisocyanate. Non-aromaticdiisocyanates may be selected from suitable members of the following,among others: 1,6-hexamethylene diisocyanate (HDI),4,4′-dicyclohexylmethane diisocyanate,3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (isophoronediisocyanate or IPDI), cyclohexyl diisocyanate, and2,2,4-trimethyl-1,6-hexamethylene diisocyanate (TMDI). In embodimentswhere diisocyanates which contain one or more one or more sites ofunsaturation are employed, examples of such diisocyanates include forexample those materials described in U.S. Pat. No. 3,505,252 toBrotherton et al., among others.

Optional chain extenders are typically aliphatic or aromatic diols (inwhich case a urethane bond is formed upon reaction with an isocyanategroup) or aliphatic or aromatic diamines (in which case a urea bond isformed upon reaction with an isocyanate group). Chain extenders may beselected from suitable members of the following, among others:alpha,omega-alkane diols such as ethylene glycol (1,2-ethane diol),1,4-butanediol, 1,6-hexanediol, alpha,omega-alkane diamines, such asethane diamine, dibutylamine (1,4-butane diamine) and 1,6-hexanediamine,or 4,4′-methylene bis(2-chloroaniline). In embodiments where chainextenders containing one or more one or more sites of unsaturation areemployed, examples of such chain extenders include the preceding diolswith one or more one or more sites of unsaturation, for example,alpha,omega-alkene diols such as 1,2-ethene diol, 1,4-butenediol,1,6-hexenediol, and so forth, or alpha,omega-alkene diamines such as1,2-ethene diamine, 1,4-butene diamine, 1,6-hexene diamine, and so forth

Chain extenders may be also selected from suitable members of thefollowing, among others: short chain diol polymers (e.g.,alpha,omega-dihydroxy-terminated polymers having a number averagemolecular weight less than or equal to 1000) based on hard or softpolymer polyisobutylene and non-polyisobutylene segments such as thosedescribed above (more typically soft polymer segments), including shortchain polyisobutylene diols, short chain polyether polyols such aspolytetramethylene oxide diols, short chain polysiloxane diols such aspolydimethylsiloxane diols, short chain polycarbonate diols such aspolyhexamethylene carbonate diols, short chain poly(fluorinated ether)diols, short chain polyester diols, short chain polyacrylate diols,short chain polymethacrylate diols, and short chain poly(vinyl aromatic)diols. In certain embodiments, such short chain diol polymers may haveone or more one or more sites of unsaturation.

As is known in the polyurethane art, chain extenders can increase thehard segment content in the urethane, urea or urethane/urea polymer (or,stated another way, can increase the ratio of hard segment material tosoft segment material in the polymer), which can in turn result in apolymer with higher modulus, lower elongation at break and increasedstrength. Such chain extenders may also be used to supply sites ofunsaturation within the polymers of the present invention as notedabove.

Polyisobutylene urethane, urea and urethane/urea copolymers inaccordance with the invention may the synthesized, for example, in bulkor using a suitable solvent (e.g., one capable or dissolving the variousspecies that participate in the polymerization reaction). In certainembodiments, polyisobutylene urethane, urea and urethane/urea copolymersin accordance with the invention are synthesized via reactive extrusion.

Various synthetic strategies may be employed to create polyisobutyleneurethane, urea and urethane/urea polymers in accordance with theinvention. These strategies typically involved the reaction of (a) oneor more polyol (commonly diol) species and one or more polyisocyanate(commonly diisocyanate) species, (b) one or more polyamine (commonlydiamine) species and one or more polyisocyanate species, or (c) one ormore polyol species, one or more polyamine species and one or morepolyisocyanate species. Reaction may be conducted, for example, neat, inorganic solvents, or using supercritical CO₂ as a solvent. Ionomers canbe used for polymer precipitation.

For example, in certain embodiments, a one step method may be employedin which a first macrodiol (M1) (e.g., a polyisobutylene diol with twoor more sites of unsaturation, etc.) and a diisocyante (DI) (e.g., MDI,TDI, etc.) are reacted in a single step. Molar ratio of diisocyanaterelative to the first macrodiol is 1:1. Using this technique apolyurethane having alternating macrodiol and diisocyante residues,i.e., -[DI-M1-]_(n), where n is an integer, may be formed. In someembodiments, a diol or diamine chain extender (CE) (e.g., 1,2-ethanediol, 1,4-butanediol, 1,6-hexanediol, etc., or a diol with one or moresites of unsaturation) is included in the reaction mixture, in whichcase the molar ratio of diisocyanate relative to the combination of thefirst macrodiol and the chain extender is 1:1. For example, the ratioDI:M1:CE may equal 2:1:1, may equal 2:1.5:0.5, may equal 2:0.5:1.5,among many other possibilities. Where a ratio of DI:M1:CE equal to 2:1:1is employed, a polyurethane having the following structure may be formed-[DI-M1-DI-CE-]_(n). Reactions of this type have been reported to followa statistical distribution, so M1 and CE residues are not likely to beperfectly alternating as shown. See, e.g., F. Wang,“Polydimethylsiloxane Modification of Segmented ThermoplasticPolyurethanes and Polyureas, Ph.D. dissertation, Virginia PolytechnicInstitute and State University, Apr. 13, 1998.

In other embodiments, a two-step reaction is employed wherein the firstmacrodiol and diisocyante are reacted in a single step at a DI:M1 molarratio of ≧2:1 in order to form isocyanate-end-capped “prepolymers,”DI-M1-DI. Then, in a second step, a chain extender is added, along withadditional diisocyanate, if required to maintain an overall molar ratioof diisocyanate relative to the combination of the first macrodiol andthe chain extender of 1:1. As above, where a molar ratio of DI:M1:CEequal to 2:1:1 is employed, a polyurethane having the followingstructure may be formed -[DI-M1-DI-CE-]_(n), although the M1 and CEresidues may not be perfectly alternating as shown. Due to enhancedreaction control, polyurethanes made by the two-step method tend to havea more regular structure than corresponding polyurethanes made by theone step method.

In certain other embodiments, a one step method may be employed in whicha first macrodiol (M1) (e.g., a polyisobutylene diol with zero, one, twoor more sites of unsaturation, etc.), a second macrodiol (M2) (e.g., apolyether diol, a fluoropolymer diol, a polysiloxane diol, apolycarbonate diol, a polyester diol, a polyacrylate diol, apolymethacrylate diol, a polystyrene diol, etc. with zero, one, two ormore sites of unsaturation) and a diisocyante (DI) (e.g., MDI, TDI,etc.) are reacted in a single step. Molar ratio of diisocyanate relativeto the first and second diols is 1:1. For example, the ratio DI:M1:M2may equal 2:1:1, may equal 2:1.5:0.5, may equal 2:0.5:1.5, among manyother possibilities. Where a ratio of DI:M1:M2 equal to 2:1:1 isemployed, a polyurethane having the following structure may be formed-[DI-M1-DI-M2-]_(n) although the chains are unlikely to be perfectlyalternating as shown. In some embodiments, a chain extender is added tothe reaction mixture, such that the molar ratio of diisocyanate relativeto the first and second macrodiols and chain extender is 1:1. Forexample, the ratio DI:M1:M2:CE may equal 4:1:1:2, may equal2:0.67:0.33:1, may equal 2:0.33:0.67:1, or may equal 5:1:1:3, among manyother possibilities. Where a ratio of DI:M1:M2:CE equal to 4:1:1:2 isemployed, a polyurethane having the following structure may be formed-[DI-M1-DI-CE-DI-M2-DI-CE-]_(n), although the chains are unlikely to beperfectly alternating as shown.

In some embodiments, a two-step method is employed in which first andsecond macrodiols and diisocyante are reacted in a ratio of DI:M1:M2 of≧2:1:1 in a first step to form isocyanate capped first and secondmacrodiols, for example DI-M1-DI and DI-M2-DI. In a second step, a chainextender is added which reacts with the isocyanate end caps of themacrodiols. In some embodiments, the number of moles of hydroxyl oramine groups of the chain extender may exceed the number of moles ofisocyanate end caps for the macrodiols, in which case additionaldiisocyante may be added in the second step as needed to maintain asuitable overall stoichiometry. As above, the molar ratio ofdiisocyanate relative to the total of the first macrodiol, secondmacrodiol, and chain extender is typically 1:1, for example, DI:M1:M2:CEmay equal 4:1:1:2, which may in theory yield an idealized polyurethanehaving the following repeat structure -[DI-M1-DI-CE-DI-M2-DI-CE-]_(n),although the chains are unlikely to be perfectly alternating as shown.In other examples, the DI:M1:M2:CE ratio may equal 4:1.5:0.5:2 or mayequal 5:1:1:3, among many other possibilities.

In some embodiments, three, four or more steps may be employed in whicha first macrodiol and diisocyante are reacted in a first step to formisocyanate capped first macrodiol, typically in a DI:M1 ratio of ≧2:1such that isocyanate end caps are formed at each end of the firstmacrodiol (although other ratios are possible including a DI:M1 ratio of1:1, which would yield an average of one isocyanate end caps permacrodiol). This step is followed by second step in which the secondmacrodiol is added such that it reacts with one or both isocyanate endcaps of the isocyanate capped first macrodiol. Depending on the relativeratios of DI, M1 and M2, this step may be used to create structures(among other statistical possibilities) such as M2-DI-M1-DI-M2 (for aDI:M1:M2 ratio of 2:1:2), M2-DI-M1-DI (for a DI:M1:M2 ratio of 2:1:1),or M1-DI-M2 (for a DI:M1:M2 ratio of 1:1:1).

In certain embodiments, a mixed macrodiol prepolymer, such as one ofthose in the prior paragraph, among others (e.g., M2-DI-M1-DI-M2,M1-DI-M2-DI-M1, DI-M1-DI-M2, etc.) is reacted simultaneously with a diolor diamine chain extender and a diisocyanate, as needed to maintainstoichiometry. For example, the chain extension process may be used tocreate idealized structures along the following lines, among others:-[DI-M2-DI-M1-DI-M2-DI-CE-]_(n),

-[DI-M1-DI-M2-DI-M1-DI-CE-]_(n) or [-DI-M1-DI-M2-DI-CE-]_(n), althoughit is again noted that the chains are not likely to be perfectlyalternating as shown. In certain other embodiments, a mixed macrodiolprepolymer is reacted with sufficient diisocyanate to form isocyanateend caps for the mixed macrodiol prepolymer (e.g., yieldingDI-M2-DI-M1-DI-M2-DI, DI-M1-DI-M2-DI-M1-DI or DI-M1-DI-M2-DI, amongother possibilities). This isocyanate-end-capped mixed macrodiol canthen be reacted with a diol or diamine chain extender (and adiisocyanate, as needed to maintain stoichiometry). For example, theisocyanate-end-capped mixed macrodiol can be reacted with an equimolaramount of a chain extender to yield idealized structures of thefollowing formulae, among others: -[DI-M2-DI-M1-DI-M2-DI-CE-]_(n),-[DI-M1-DI-M2-DI-M1-DI-CE-]_(n) or -[DI-M1-DI-M2-DI-CE-]_(n).

Using the above and other techniques, a wide variety of crosslinkablepolyisobutylene polymers, including various urethanes, ureas andurethane/ureas can be formed. Typical number average molecular weightsfor the crosslinkable polyisobutylene polymers within the crosslinkablecompositions of the invention range from 1,000 to 300,000 daltons, amongother values, for instance, ranging from 1,000 to 2,000 to 5,000 to10,000 to 15,000 to 20,000 to 25,000 to 50,000 to 100,000 to 300,000Daltons. Durometer values, which are influenced, for example, by thetype of diisocyanate and by the ratio of hard segments to soft segmentsin the polymer (which is in turn influenced, for example, by the lengthof the soft segments in the polymer and the degree of chain extension,if any), can vary widely, and typically ranges from 10 A to 75 D, forinstance, range from 10 A to 20 A to 30 A to 40 A to 50 A to 60 A to 70A to 80 A to 90 A to 100 A (=58 D) to 60 D to 65 D to 70 D to 75 D.

In various aspects of the invention, crosslinkable compositions areprovided, which comprise (a) one or more types of crosslinkablepolyisobutylene polymers and (b) one or more optional supplementalagents such as (i) therapeutic agents (numerous examples of which aredescribed below) and (ii) chemical agents that promote crosslinking(“crosslinking agents”) such as catalysts, initiators includingphotoinitiators, redox initiators and heat labile initiators,accelerators, hardening agents, and additional unsaturated polymers, andso forth and (iii) fluoroscopy markers, among others.

Crosslinking may progress with the aid of suitable crosslinking species,for example, species that aid in completion of a chemical reactionwithout becoming part of the reaction product (e.g., catalysts,accelerators, etc.) and/or species that become part of the crosslinkedpolymer network (e.g., initiators, hardening agents, additionalmonomers, polymers, etc.), among others.

Crosslinking may be initiated by exposure to energy (e.g., theapplication of heat or ionizing or non-ionizing radiation such as e-beamradiation, gamma radiation, UV light, etc.), a chemical agent (e.g.,moisture, a hardening agent, etc.), or both.

Examples of initiators include free-radical generating species, whichmay be activated or accelerated by the application of heat (i.e.,thermal initiators, such as peroxide initiators, azo initiators, etc.)and/or light (i.e., photoinitiators, such as benzoin ethers, arylketones, acyl phosphine oxides, etc.).

Examples of peroxide initiators for thermal initiation include thefollowing: benzoyl peroxide, t-amyl peracetate,2,5-dimethyl-2,5-bis(t-butylperoxy)-3-hexyne,2,5-dimethyl-2,5-di-(t-butylperoxy)-hexane, t-butyl alpha-cumylperoxide, di-butyl peroxide, t-butyl hydroperoxide, dichlorobenzoylperoxide, dicumyl peroxide, di-t-butyl peroxide, 2,5dimethyl-2,5-di(peroxy benzoate)-3-hexyne, 1,3-bis(t-butyl peroxyisopropyl) benzene, lauroyl peroxide, di-t-amyl peroxide,1,1-di-(t-butylperoxy) cyclohexane, 2,2-di-(t-butylperoxy) butane, and2,2-di-(t-amylperoxy) propane.

Azo compounds such as 2,2′-azobisisobutyronitrile (AIBN) and V-50 andV-086 from Wako Specialty Chemicals, or AZDN, AIVN, and Azocarboxy fromArkema, among others, may also be employed for thermal initiation.

Specific examples of photoinitiators include benzoin ether, benzildimethyl ketone acetal, 1-hydroxycyclohexyl phenyl ketone,2-hydroxy-2-methyl-1-phenyl-propane-1-one, diethoxyacetophenone,benzophenone, methylthioxanone, 2,4,6,trimethylbenzoyl diphenylphosphine oxide (TPO), acyl phosphine oxide (APO) and bis acyl phosphineoxide (BAPO).

Without wishing to be bound by theory, it is believed that a freeradical initiator forms a radical, which attacks a carbon-carbon doublebond within another entity (e.g., a carbon-carbon double bond with acrosslinkable polyisobutylene polymer of the invention) forming aradical in that entity. Once formed, a radical on one entity may, forexample, attack a double bond in another entity (e.g., in anothercrosslinkable polymer) forming a chemical bond between the entities anda new radical center. Alternatively, radicals on two different entitiesmay combine to form a bond between the entities without the creation ofa new radical center (a process called combination). Regardless of theprecise reaction mechanism, crosslinks are created between the entities.The resulting crosslinks are based on the formation of carbon-carbonbonds, without the formation of functional groups (e.g., ester, amide,etc.) that are prone to hydrolysis and other forms of degradation.

Crosslinking may be enhanced when the polymer is in a mobile state, forexample, in a melt state, which state may be established concurrentlywith radical formation, or subsequent to radical formation.

Free radical crosslinking reactions may also be promoted by theintroduction of multifunctional crosslinking agents having two or moresites of unsaturation (e.g., —HC═CH—, —HC═CH₂, —C≡C— or —C≡CH). Forexample, in some embodiments of the invention, vinyl crosslinking agentsmay be added to enhance crosslinking between the polymers. For instance,alkenes such as HC═CH—(CH₂)_(n)—HC═CH or HC═CH—[CH₂—C(CH₃)₂]_(n)—HC═CH,where n is an integer, for example, ranging from 0 to 20, may be usedfor this purpose. Note that the latter species is a short (e.g., 20monomers or less) terminally unsaturated polyisobutylene crosslinkingagent. In this regard, compatibility between the crosslinking agents andthe polymers of the invention may be enhanced by using multifunctionalcrosslinking agents that contain polymer blocks which have the same orsimilar monomer composition as is found in the polymer to becrosslinked. In other embodiments, short terminally unsaturated polymerscorresponding to any additional blocks used within the polymers of theinvention may be employed as crosslinking agents (e.g., short terminallyunsaturated polyether segments, poly(acrylate) segments,poly(methacrylate) segments, polysiloxane segments, polycarbonatesegments, etc.).

Additional examples of multifunctional crosslinking agents includepolymers containing unsaturation along the backbone, for example,poly(butadiene), which can crosslink with the polyisobutylene urethane,urea or urethane/urea copolymer, and unsaturated monomers that canpolymerize during the crosslinking reaction. These monomers may havefunctionality built in, for example, containing epoxide groups, carboxylgroups or hydroxyl groups, among others.

Other crosslinking strategies besides free-radical based crosslinkingstrategies may be employed in conjunction with the invention. Forexample, a peroxyacid, for instance, a peroxy-carboxylic acid such asmeta-chloroperoxybenzoic acid (mCPBA), among others, may be used tooxidize carbon-carbon double bonds in the polymers of the invention togenerate epoxide groups (oxiranes). The resulting epoxide-containingpolymer may be crosslinked by exposure to radiation (either ionizing ornon-ionizing). The resulting epoxide-containing polymer may also becrosslinked by exposure to a curing agent, for instance, amultifunctional amine such as triethylenetetramine (TETA) ordifunctional amines such as are described below. When these are mixedtogether, the amine groups react with the epoxide groups to form acovalent bond.

As another example, crosslinking may be achieved by use of “click”chemistry. Typical reactions include reaction of terminal alkynes withazides, reaction of activated nitriles such as toluenesulfonyl cyanidewith unhindered azides, or nucleophilic ring opening reactions ofstrained rings such as epoxides, aziridines or cyclic sulfates. Thealkynes can be pendant groups at any location in the polyisobutyleneurethane, urea or urethane/urea copolymer (collectively PIBPU), forexample, in the PIB segments, or in the diisocyanate segments. In atypical crosslinking reaction, a PIB PU with pendant alkynes would bereacted with an aliphatic or aromatic diazide. Alternately, reaction ofepoxide rings in the backbone of the PIB PU with diamines will result incrosslinking through ring opening polymerization.

As yet another example, crosslinking may be achieved by hydrosilation.Hydrosilation involves the addition of a Si—H bond across an unsaturatedcarbon-carbon bond. This addition is catalyzed by noble metals,typically platinum. An example of a crosslinking agent useful for thispurpose is a multifunctional silicon hydride.

As another example, crosslinking may be achieved by firsthydrosilylating unsaturated polymers such as those described herein witha silane compound, whereupon the silicon hydride bond (Si—H) reacts withthe pendant olefinic unsaturation found in the polymer. As above, thisreaction may be catalyzed by noble metals, typically platinum. Thesilane also contains one or more alklysiloxy groups for subsequentcrosslinking reactions in this embodiment. An example of such a compoundis tris(trimethylsiloxy)silane available from Sigma-Aldrich. Otherexamples include species of the formula SiH_(n)(OR)_(4-n), where n is aninteger of 1, 2 or 3 and R is selected from branched and unbanked alkylgroups having 1 to 10 carbon atoms and aryl groups having 6 to 10 carbonatoms. Such polymers are moisture curable (crosslinkable). Inparticular, crosslinking may proceed upon exposure to water, whichcauses the alkoxy groups in the polymer to be hydrolyzed, followed bycondensation of neighboring hydroxyl groups to form the crosslinkscontaining —Si—O—Si— linkages. This process may be promoted, forexample, by steam autoclaving or through the use of a suitable catalyst,for example an organo-tin catalyst.

In other embodiments, crosslinking may be achieved using polymers withterminal groups such as glycidyl or carboxylic acid groups. In suchcases, the resultant crosslinked adhesive materials will be epoxides oresters and will be moisture cured in the presence or absence of heat.

As seen from the above, in certain embodiments, compositions inaccordance with the invention may be crosslinked upon contact with asuitable multifunctional crosslinking agent such as a multifunctionalamine, multifunctional epoxide, or a multifunctional silicon hydride,among others. In those embodiments, a composition comprising acrosslinkable polyisobutylene-based polymer in accordance with theinvention may be provided in a first container and a multifunctionalcrosslinking agent (e.g., multifunctional amine, multifunctional siliconhydride, etc.) may be provided in a second container in the form of akit.

In certain embodiments of the invention, crosslinkable compositions inaccordance with the present invention are applied to one or more medicaldevice components (e.g., as a coating on a medical device component oras an adhesive for attaching two or more medical device components) andthen cured under suitable conditions (e.g., exposure to heat, radiation,multifunctional crosslinking agent, atmospheric moisture, etc.). Lowmolecular weight PIBPU with terminal double bonds and a free radicalinitiator is one of the several possibilities. Another possibility isPIBPU with terminal double bonds, a second low molecular weightpolymer/oligomer with double bonds, and a free radical initiator.

Crosslinkable compositions in accordance with the present invention areparticularly beneficial as coatings or adhesives for polyisobutylenecontaining polymers, for example, thermoplastic polyisobutylenecopolymers such as those having one or more polyisobutylene segment andone or more hard segments. Examples of such copolymers include blockcopolymers having one or more polyisobutylene segment and one or morehard segment, for instance, selected from those described above (e.g.,poly(vinyl aromatic), poly(alkyl acrylate) or poly(alkyl methacrylate)hard segments such as polystyrene, poly(tert-butyl acrylate) andpoly(methyl methacrylate), among others. Specific examples of suchpolymers include triblock copolymers having a soft segment between twohard segments, for instance, poly(styrene-b-isobutylene-b-styrene),poly(tert-butyl acrylate-b-isobutylene-b-tert-butyl acrylate) andpoly(methyl methacrylate-b-isobutylene-b-methyl methacrylate), amongothers.

Examples of such copolymers further include polyisobutylene containingpolyurethanes, polyureas or polyurethane/polyureas, which may beprepared, for example, using techniques like those described above(except that the polyisobutylene, diisocyanate, and optional componentssuch as chain extenders and non-polyisobutylene polymeric componentsneed not contain one or more sites of unsaturation). Examples thusinclude polyurethanes, polyureas and polyurethane/polyureas having oneor more polyisobutylene soft segments, one or more segments arising fromaromatic diisocyanates (e.g., MDI, TDI, NDI, etc.), and one or moreoptional segments (e.g., segments arising from chain extenders and/ornon-polyisobutylene polymer segments which may be selected, forinstance, from those set forth above, among others).

As a specific example, crosslinkable compositions in accordance with thepresent invention may be used to coat or adhere one or more components,which one or more components contain a thermoplastic polyisobutyleneurethane, urea or urethane/urea copolymer that comprises one or morepolyisobutylene segments and one or more polytetramethylene oxidesegments (e.g., a copolymer formed from polyisobutylene diol,polyhexamethylene oxide or polyhexamethylene oxide diol, MDI as adiisocyante and 1,4-butane diol as a chain extender, among otherpossibilities), for instance having a number average molecular weight ofat least 1000 Daltons.

Where a crosslinkable composition of the invention is applied to amaterial comprising a non-polyisobutylene polymer segment (e.g., apolyether segment, polyacrylate segment, polymethacrylate segment,polyvinyl aromatic segment, polysiloxane segment, polycarbonate segment,etc.), in certain embodiments, the crosslinkable composition willcontain a matching non-polyisobutylene entity (i.e., one with the samemonomer content). For example, a matching non-polyisobutylene segmentmay be provided as a segment within the crosslinkable polyisobutylenepolymer in the composition or it may be provided within a separateentity in the composition, for example, a crosslinking agent comprisingsuch a non-polyisobutylene segment with terminal unsaturation may beincluded in the composition, among other possibilities. In a specificexample, a polysiloxane segment (e.g., a polydimethylsiloxane segment)may be provided in the composition to enhance adhesion to silicone. Sucha composition can be used, for example, to bond silicone to silicone orto bond silicone to a polyisobutylene-containing polymer.

In a specific example, crosslinkable compositions in accordance with theinvention may comprise a low molecular weight polyisobutylene urethane,urea or urethane/urea copolymer (e.g., having a number average molecularweight ranging between 1000 and 50,000 Daltons, for instance rangingfrom 1,000 to 2,500 to 5,000 to 10,000 to 25,000 to 50,000 Daltons)which contains one or more polyisobutylene segments and two or moresites of unsaturation, along with any optional agents such ascrosslinking agents, therapeutic agents and so forth (e.g., acomposition comprising a copolymer formed from a divinyl or diallylpolyisobutylene diol, MDI as a diisocyanate and 1,4-butane diol as achain extender and comprising as a crosslinking agent an organicperoxide (aromatic/aliphatic) such as dicumyl peroxide or benzoylperoxide, a ketone such as benzophenone or methylphenyl ketone, anorganic azide such as AIBN, or an organometallic catalyst such as aplatinum complex).

As another specific example, crosslinkable compositions in accordancewith the invention may comprise a low molecular weight polyisobutyleneurethane, urea or urethane/urea copolymer (e.g., having a number averagemolecular weight ranging between 1,000 and 50,000 Daltons, for instance,ranging from 1,000 to 2,500 to 5,000 to 10,000 to 25,000 to 50,000Daltons) which contains one or more polyisobutylene segments, one ormore non-polyisobutylene polymer segments (e.g., one or morepolytetramethylene oxide segments, etc.) and two or more sites ofunsaturation, along with any optional agents such as crosslinkingagents, therapeutic agents and so forth (e.g., a composition comprisinga copolymer formed from a divinyl or diallyl polyisobutylene diol,polytetramethylene oxide diol, MDI as a diisocyanate and 1,4-butane diolas a chain extender and comprising as a crosslinking agent an organicperoxide (aromatic/aliphatic) such as dicumyl peroxide or benzoylperoxide, an organic azide such as AIBN, or an organometallic catalystsuch as a platinum complex).

As yet another specific example, crosslinkable compositions inaccordance with the invention may comprise a low molecular weightpolyisobutylene urethane, urea or urethane/urea copolymer (e.g., havinga number average molecular weight ranging between 1,000 and 50,000Daltons) which contains one or more polyisobutylene segments and two ormore sites of unsaturation, anon-polyisobutylene-polymer-segment-containing crosslinking agent (e.g.,a polytetramethylene oxide crosslinking agent having two or more sitesof unsaturation), along with any optional agents such as crosslinkingagents, therapeutic agents and so forth (e.g., a composition comprising(a) a copolymer formed from a divinyl or diallyl polyisobutylene diol,MDI as a diisocyante and 1,4-butane diol as a chain extender and (b) acrosslinking agent, for example, divinyl polytetramethylene oxide, anorganic peroxide (aromatic/aliphatic) such as dicumyl peroxide orbenzoyl peroxide, a ketone such as benzophenone or methylphenyl ketone,an organic azide such as AIBN and/or an organometallic catalyst such asa platinum complex, among others).

In certain embodiments, crosslinkable compositions in accordance withthe present invention are used to form medical device components, forexample, by molding or by reactive extrusion. For instance, in someembodiments, a crosslinkable composition in accordance with the presentinvention may be introduced into a mold and cured, for example, byheating or by exposure to radiation (e.g., using a mold that can bepenetrated by the radiation of interest), or a crosslinkable compositionin accordance with the present invention may be introduced into a moldalong with a chemical species that leads to crosslinking (e.g.,water/moisture, a multifunctional crosslinking agent, etc.) Suchproducts will frequently have a seam or other evidence of having beenmolded, but not necessarily in every case.

In other embodiments, a crosslinkable composition in accordance with thepresent invention may be extruded in a reactive extrusion process,wherein the heat of the extrusion process leads to crosslinking orwherein a chemical species that leads to crosslinking (e.g.,water/moisture, multifunctional crosslinking agent, etc.) is introducedinto the extruder at suitable point along the extruder barrel.

In certain embodiments, crosslinkable compositions in accordance withthe present invention are used to form a coating on a medical devicecomponent. For instance, in some embodiments, a crosslinkablecomposition in accordance with the present invention may be applied to amedical device component and cured, for example by overmolding, byheating, by exposure to radiation, or by admixing with a chemicalspecies that leads to crosslinking (e.g., water/moisture, amultifunctional crosslinking agent, organometallic complex, etc.)

In certain embodiments, crosslinkable compositions in accordance withthe present invention are used to attach two or more medical devicecomponents to one another. For instance, in some embodiments, acrosslinkable composition in accordance with the present invention ispositioned between two or more medical device components and cured, forexample, by heating, by exposure to radiation, or by admixing with achemical species that leads to crosslinking (e.g., water/moisture, amultifunctional crosslinking agent, etc.) For example, crosslinkablecompositions in accordance with the present invention may be used toattach a silicone component to a silicone component, to attach asilicone component to a polyurethane component, to attach a polyurethanecomponent to a polyurethane component, to attach a polyisobutylenepolymer (e.g., a polyisobutylene homopolymer or copolymer, for instance,a block copolymer, polyurethane, polyurea, polyurethane/urea, and soforth) component to a polyisobutylene polymer component, to attach apolyisobutylene polymer component to a silicone component, to attach apolyisobutylene polymer component to a non-polyisobutylene polyurethanecomponent, and so forth. In many of these embodiments, the crosslinkablecompositions will contain a polymeric segment that is common to eachcomponent to maximize compatibility (e.g., a polydimethylsiloxanesegment when bonding a silicone component, a polyisobutylene segmentwith bonding a polyisobutylene polymer component, etc.)

More generally, in accordance with various aspects of the invention,implantable and insertable medical devices are provided, which containone or more polymeric regions containing one or more crosslinkedpolyisobutylene polymers (e.g., one or more crosslinked polyisobutyleneurethane, urea or urethane/urea copolymers). As used herein, a“polymeric region” is a region (e.g., an entire device, a devicecomponent, a device coating layer, an adhesive region with a device,etc.) that contains polymers, for example, from 50 wt % or less to 75 wt% to 90 wt % to 95 wt % to 97.5 wt % to 99 wt % or more polymers.

As indicated above, in some embodiments, the polymeric regions of thepresent invention correspond to an entire medical device. In otherembodiments, the polymeric regions correspond to one or more portions ofa medical device. For instance, the polymeric regions can be in the formof medical device components, in the form of one or more fibers whichare incorporated into a medical device, in the form of one or morepolymeric layers formed over all or only a portion of an underlyingmedical device or device component, in the form of an adhesive regionthat attaches two or more other medical device components to oneanother, and so forth.

Examples of medical devices for the practice of the present inventioninclude implantable or insertable medical devices, for example,implantable electrical stimulation systems including neurostimulationsystems such as spinal cord stimulation (SCS) systems, deep brainstimulation (DBS) systems, peripheral nerve stimulation (PNS) systems,gastric nerve stimulation systems, cochlear implant systems, and retinalimplant systems, among others, cardiac systems including implantablepacemaker systems, implantable cardioverter-defibrillators (ICD's), andcardiac resynchronization and defibrillation (CRDT) devices, includingpolymeric components for leads including lead insulation, outer bodyinsulation, and components for the foregoing implantable electricalstimulation systems, stents (including coronary vascular stents,peripheral vascular stents, cerebral, urethral, ureteral, biliary,tracheal, gastrointestinal and esophageal stents), stent coverings,stent grafts, vascular grafts, valves including heart valves andvascular valves, abdominal aortic aneurysm (AAA) devices (e.g., AAAstents, AAA grafts, etc.), vascular access ports, dialysis ports,embolization devices including cerebral aneurysm filler coils (includingGuglilmi detachable coils and metal coils), embolic agents, tissuebulking devices, catheters (e.g., renal or vascular catheters such asballoon catheters and various central venous catheters), guide wires,balloons, filters (e.g., vena cava filters and mesh filters for distilprotection devices), septal defect closure devices, myocardial plugs,patches, ventricular assist devices including left ventricular assisthearts and pumps, total artificial hearts, shunts, anastomosis clips andrings, and tissue engineering scaffolds for cartilage, bone, skin andother in vivo tissue regeneration (e.g., porous scaffolds, electrospunfilms and membranes for tissue integration), urethral slings, hernia“meshes”, artificial ligaments, orthopedic prosthesis, one grafts,spinal disks, dental implants, biopsy devices, as well as any coatedsubstrate (which can comprise, for example, metals, polymers, ceramicsand combinations thereof) that is implanted or inserted into the body.

In certain preferred embodiments, crosslinkable polyisobutylene polymersin accordance with the present invention may be used to form leadinsulation components through which at least one conductor extends,including single-lumen and multi-lumen extrusions and tubular(tube-shaped) insulation layers, and inner and outer coatings forimplantable electrical leads, or they may be used to form various otherlead components (e.g., O-ring seals, drug delivery collars, lead tipmaterials, lead terminal pins, headers, etc.).

In certain embodiments, crosslinkable polyisobutylene polymers inaccordance with the present invention may be used to form polymericcomponents of electronic signal generating/sensing components, examplesof which include implantable pulse generators, implantablecardioverter-defibrillators (ICDs) and implantable cardiacresynchronization therapy (CRT) devices. Such electronic signalgenerating/sensing components may be used, for example, in conjunctionwith right ventricular lead systems, right atrial lead systems, and leftatrial/ventricular lead systems and may be used to treat, for example,bradycardia, tachycardia (e.g., ventricular tachycardia) or cardiacdyssynchrony in a vertebrate subject (including humans, pets andlivestock). Specific examples of such polymeric components includeconnectors (plugs) for “cans” (i.e., housings that contain electronicsignal generating/sensing components), seals (coatings) for cans, drugdelivery collars, delivery collars, plugs, passive fixation tip/tines,tip assemblies, molded seals, and suture sleeves, among many otherapplications.

Single-lumen and multi-lumen components may be formed, for example, byreactive extrusion. Discrete components such as O-ring seal, lead tipmaterials, lead terminal pins, headers, connectors (plugs), drugdelivery collars, drug delivery plugs, or any other component currentlymolded from silicone or polyurethane, among others, may be formed, forexample, by molding.

Low Durometer materials (e.g., 40 A to 70 A Shore hardness) may bepreferred for components such as seals, neck joint, passive fixationtines. Such low Durometer materials may be formed using any of the abovecrosslinkable polyisobutylene polymers including urethane, urea andurethane/urea copolymers with little or no chain extension in presenceof a cross-linker and a crosslinking agent. Medium Durometer materials(e.g., 70 A to 85 A Shore Hardness) may be preferred for components suchas lead tips, and connectors amongst others. High Durometer materials(e.g., 85 A to 75 D Shore Hardness scale) may be preferred forcomponents such as terminal pins, device headers, etc.

Typical applications in leads where it is desirable to connect onecomponent to another using the adhesives of the invention includevarious polymer-to-polymer and polymer-to-metal joints, moreparticularly, header to set screw seals, port seals, terminal ringseals, drug collar bonds, all joints in the IS-4 terminal, the pigtailjoint cable, polyurethane boot to terminal and potting, tip totubing-neck region (Reliance IS-1 and IS-4), terminal region in pacingleads, SST terminal ring to seal in pacing leads, bonds with thetitanium (Reliance IS-1 and IS-4), bonds in the terminal and in thedistal transition regions, header to titanium cans, and so forth.

Various known polyurethanes presently used in the medical device art(such as polyether, polyester, and polycarbonate based polyurethanesand/or their blends/copolymers with polydimethylsiloxane) can eventuallyexhibit environmental stress cracking upon insertion into a patient'sbody, due to the harsh (e.g., oxidative, hydrolytic, enzymatic, etc.)conditions that are encountered there. Where such polyurethanes areemployed as lead insulation materials, such cracking can cause a breachin the insulation that allows bodily fluids to enter the lead and formshorts, for example, between the conductor(s) and/or the electroniccomponents that generate current through the conductor(s). Moreover,slow corrosion of the metal conductor(s) within electrical leads isoften encountered in the in vivo environment. The metal ions thusgenerated from the slow corrosion process are known to react withvarious insulation materials, including polyurethanes, causing metal ionoxidation (MIO) that can result in degradation and deterioration of thematerial. This can lead to rapid battery depletion and affect theability of the device to reliably provide therapy.

The polyisobutylene urethane, urea and urethane/urea copolymers inaccordance with the present invention, on the other hand, are believedto possess enhanced biostability and biocompatibility. In this regard,it is believed that the polyisobutylene segments within the copolymer ofthe invention are highly resistant to degradation (e.g., oxidative,hydrolytic, enzymatic, metal ion, etc.) relative to known polyurethanesoft segments such as polyether, polyester, and polycarbonate basedpolyurethanes and/or their blends/copolymers with polydimethylsiloxane.Polyisobutylene is also known to have good barrier properties and isbiocompatible.

Because the materials of the invention have good structural andelectrical characteristics, good biostability and good biocompatibility,in certain embodiments, a single extrusion may be employed as a leadinsulation material without the need for inner and outer coatings. Incertain embodiments, a single extrusion may be formed which varies inDurometer along its length. For example, the extrusion may vary from 40A at or near the distal tip (to provide flexibility for lead tipnavigation) to 100 A at or near the proximal end of the extrusion (toprovide stiffness for lead advancement). In one specific example, theDurometer of the material may be changed by changing the relativeamounts of the polyisobutylene diol, optional non-polyisobutylene diol,diisocyanate and chain extender during the course of reactive extrusion.Durometer can also be changed by changing the amount of crosslinkingagent that is provided during the course of extrusion.

As noted above, in addition to crosslinked polyisobutylene polymers, thepolymeric regions for use in the medical devices of the presentinvention may optionally contain one or more supplemental agents.

For example, in some embodiments, an organically modified silicate isblended with the polymers forming the polymeric region as a supplementalagent. Such an agent may act to create a tortuous pathway for moisturethereby decreasing the moisture permeability of the region. Moreover,such silicates may maintain the strength and increase the modulus of thematerial. Supplemental agents further include agents such as alumina,silver nanoparticles, and silicate/alumina/silver nanoparticlecomposites. Supplemental agents further include fluoroscopy markers suchas calcium tungstate and other tungsten based compositions, amongothers.

In some embodiments, one or more therapeutic agents are includedbeneath, within (e.g., blended with), or attached to (e.g., covalentlyor non-covalently bound to) polymeric regions in accordance with theinvention. “Therapeutic agents,” “drugs,” “pharmaceutically activeagents,” “pharmaceutically active materials,” and other related termsmay be used interchangeably herein.

A wide variety of therapeutic agents can be employed in conjunction withthe present invention including those used for the treatment of a widevariety of diseases and conditions (i.e., the prevention of a disease orcondition, the reduction or elimination of symptoms associated with adisease or condition, or the substantial or complete elimination of adisease or condition).

Exemplary therapeutic agents for use in conjunction with the presentinvention include the following: (a) anti-thrombotic agents such asheparin, heparin derivatives, urokinase, clopidogrel, and PPack(dextrophenylalanine proline arginine chloromethylketone); (b)anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine and mesalamine; (c)antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, angiopeptin, monoclonal antibodies capable ofblocking smooth muscle cell proliferation, and thymidine kinaseinhibitors; (d) anesthetic agents such as lidocaine, bupivacaine andropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors(e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; (o) agents thatinterfere with endogenous vasoactive mechanisms; (p) inhibitors ofleukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r)hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein,which is a molecular chaperone or housekeeping protein and is needed forthe stability and function of other client proteins/signal transductionproteins responsible for growth and survival of cells) includinggeldanamycin, (t) alpha receptor antagonist (such as doxazosin,Tamsulosin) and beta receptor agonists (such as dobutamine, salmeterol),beta receptor antagonist (such as atenolol, metaprolol, butoxamine),angiotensin-II receptor antagonists (such as losartan, valsartan,irbesartan, candesartan and telmisartan), and antispasmodic drugs (suchas oxybutynin chloride, flavoxate, tolterodine, hyoscyamine sulfate,diclomine) (u) bARKct inhibitors, (v) phospholamban inhibitors, (w)Serca 2 gene/protein, (x) immune response modifiers includingaminoquizolines, for instance, imidazoquinolines such as resiquimod andimiquimod, (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV,etc.), (z) selective estrogen receptor modulators (SERMs) such asraloxifene, lasofoxifene, arzoxifene, miproxifene, ospemifene, PKS 3741,MF 101 and SR 16234, (aa) PPAR agonists, including PPAR-alpha, gamma anddelta agonists, such as rosiglitazone, pioglitazone, netoglitazone,fenofibrate, bexaotene, metaglidasen, rivoglitazone and tesaglitazar,(bb) prostaglandin E agonists, including PGE2 agonists, such asalprostadil or ONO 8815Ly, (cc) thrombin receptor activating peptide(TRAP), (dd) vasopeptidase inhibitors including benazepril, fosinopril,lisinopril, quinapril, ramipril, imidapril, delapril, moexipril andspirapril, (ee) thymosin beta 4, (ff) phospholipids includingphosphorylcholine, phosphatidylinositol and phosphatidylcholine, (gg)VLA-4 antagonists and VCAM-1 antagonists, (hh) non-fouling, proteinresistant agents such as polyethyelene glycol and (ii) prohealingagents.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis (antirestenotics).Such agents are useful for the practice of the present invention andinclude one or more of the following: (a) Ca-channel blockers includingbenzothiazapines such as diltiazem and clentiazem, dihydropyridines suchas nifedipine, amlodipine and nicardapine, and phenylalkylamines such asverapamil, (b) serotonin pathway modulators including: 5-HT antagonistssuch as ketanserin and naftidrofuryl, as well as 5-HT uptake inhibitorssuch as fluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/Guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including α-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists such as bosentan, sitaxsentan sodium, atrasentan,endonentan, (f) nitric oxide donors/releasing molecules includingorganic nitrates/nitrites such as nitroglycerin, isosorbide dinitrateand amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,S-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such ascilazapril, fosinopril and enalapril, (h) ATII-receptor antagonists suchas saralasin and losartin, (i) platelet adhesion inhibitors such asalbumin and polyethylene oxide, (j) platelet aggregation inhibitorsincluding cilostazole, aspirin and thienopyridine (ticlopidine,clopidogrel) and GP IIb/IIIa inhibitors such as abciximab, epitifibatideand tirofiban, (k) coagulation pathway modulators including heparinoidssuch as heparin, low molecular weight heparin, dextran sulfate andβ-cyclodextrin tetradecasulfate, thrombin inhibitors such as hirudin,hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and argatroban,FXa inhibitors such as antistatin and TAP (tick anticoagulant peptide),Vitamin K inhibitors such as warfarin, as well as activated protein C,(l) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,flurbiprofen, indomethacin and sulfinpyrazone, (m) natural and syntheticcorticosteroids such as dexamethasone, prednisolone, methprednisoloneand hydrocortisone, (n) lipoxygenase pathway inhibitors such asnordihydroguairetic acid and caffeic acid, (o) leukotriene receptorantagonists, (p) antagonists of E- and P-selectins, (q) inhibitors ofVCAM-1 and ICAM-1 interactions, (r) prostaglandins and analogs thereofincluding prostaglandins such as PGE1 and PGI2 and prostacyclin analogssuch as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost,(s) macrophage activation preventers including bisphosphonates, (t)HMG-CoA reductase inhibitors such as lovastatin, pravastatin,atorvastatin, fluvastatin, simvastatin and cerivastatin, (u) fish oilsand omega-3-fatty acids, (v) free-radical scavengers/antioxidants suchas probucol, vitamins C and E, ebselen, trans-retinoic acid SOD(orgotein) and SOD mimics, verteporfin, rostaporfin, AGI 1067, andM40419, (w) agents affecting various growth factors including FGFpathway agents such as bFGF antibodies and chimeric fusion proteins,PDGF receptor antagonists such as trapidil, IGF pathway agents includingsomatostatin analogs such as angiopeptin and ocreotide, TGF-β pathwayagents such as polyanionic agents (heparin, fucoidin), decorin, andTGF-β antibodies, EGF pathway agents such as EGF antibodies, receptorantagonists and chimeric fusion proteins, TNF-α pathway agents such asthalidomide and analogs thereof, Thromboxane A2 (TXA2) pathwaymodulators such as sulotroban, vapiprost, dazoxiben and ridogrel, aswell as protein tyrosine kinase inhibitors such as tyrphostin, genisteinand quinoxaline derivatives, (x) matrix metalloprotease (MMP) pathwayinhibitors such as marimastat, ilomastat, metastat, batimastat, pentosanpolysulfate, rebimastat, incyclinide, apratastat, PG 116800, RO 1130830or ABT 518, (y) cell motility inhibitors such as cytochalasin B, (z)antiproliferative/antineoplastic agents including antimetabolites suchas purine analogs (e.g., 6-mercaptopurine or cladribine, which is achlorinated purine nucleoside analog), pyrimidine analogs (e.g.,cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards,alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,doxorubicin), nitrosoureas, cisplatin, agents affecting microtubuledynamics (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxeland epothilone), caspase activators, proteasome inhibitors, angiogenesisinhibitors (e.g., endostatin, angiostatin and squalamine), sirolimus,everolimus, tacrolimus, zotarolimus, biolimus, cerivastatin,flavopiridol and suramin, (aa) matrix deposition/organization pathwayinhibitors such as halofuginone or other quinazolinone derivatives,pirfenidone and tranilast, (bb) endothelialization facilitators such asVEGF and RGD peptide, (cc) blood rheology modulators such aspentoxifylline and (dd) glucose cross-link breakers such as alagebriumchloride (ALT-711).

Where a therapeutic agent is present, a wide range of loadings may beused in conjunction with the medical devices of the present invention.Typical therapeutic agent loadings range, for example, from than 1 wt %or less to 2 wt % to 5 wt % to 10 wt % to 25 wt % or more of thepolymeric region.

EXAMPLES Example 1

A polyisobutylene (PIB) derivative with terminal unsaturation having anumber average molecular weight ranging from 100 to 100,000 Daltons isinitially synthesized, for example, selected from the following:

where n is an integer ranging from 1 to 50. The PIB derivative withterminal unsaturation is then extruded, molded (e.g., injection molded),or applied on or between two or more components to be bonded or joined,either by itself or with a suitable crosslinking agent, such as a UVinitiator (e.g., benzophenone, benzoyl peroxide, AIBN, etc.) or athermal initiator (e.g., a peroxide such as dicumyl peroxide) or anorganometallic catalyst (e.g., a platinum catalyst) or any other knowncross-linking agent. The resulting composition is then crosslinked usingheat or using radiation (e.g., UV-Visible light, electron beam, gammabeam, laser irradiation, etc.), moisture or a metal catalyst, either atroom temperature or elevated temperature.

Example 2

A polyisobutylene (PIB) derivative having a number average molecularweight ranging from 100 to 100,000 Daltons with suitable terminalreactive groups is initially synthesized, for example, selected from thefollowing:

where n is an integer ranging from 1 to 50, and X is selected from —OH,—NH₂, —COOH, —COOCH₂CH₃, —CHOCH₂ (epoxide), —N═C═O, —O[Si(R)₂O]_(m)H,where m ranges from 1 to 100 and R is lower alkyl (e.g., —CH₃, —C₂H₅,etc.), —OSi(R)₃ where R is lower alkoxy (e.g., acetoxy), —CH═CH₂,—CH≡CH, —OC(═O)C(CH₃)═CH₂, —OC(═O)C(H)═CH₂ and—OC(═O)OCH₂(CH₂)_(p)CH═CH₂, wherein p ranges from 1 to 10, as well as—O[Si(R)₂O]_(m)—(CH₂)_(p)—CH═CH₂, —O[Si(R)₂O]_(m)—(CH₂)_(p)—C≡CH,—O[Si(R)₂O]_(m)—[CH₂C(CH₃)₂]_(q)—(CH₂)_(p)—C≡CH and—O[Si(R)₂O]_(m)—[CH₂₋C(CH₃)₂]_(q)—(CH₂)_(p)CH═CH₂ where m ranges from 2to 100, p ranges from 1 to 10 and q ranges from 2 to 25.

When X is, for example, —OH, —NH₂ or —COOH, an organic crosslinkingagent with two or more terminal isocyanate as functional groups may beemployed. The organic crosslinking agent may be, for example, aromaticor aliphatic (e.g., linear, branched or hyper-branched aliphatic) or acombination of the preceding. The crosslinking reaction may be carriedout either at room temperature or at elevated temperature.

When X is, for example, —N═C═O an organic crosslinking agent with two ormore terminal —OH, —NH₂ or —COOH groups may be employed. The organiccrosslinking agent may be, for example, aromatic or aliphatic (e.g.,linear, branched or hyper-branched aliphatic) or a combination of thepreceding. The crosslinking reaction may be carried out either at roomtemperature or at elevated temperature.

When X comprises terminal unsaturation, for example, where X is—O[Si(R)₂O]_(n), —CH═CH₂, —O[Si(R)₂O]_(m)—(CH₂)_(p)—CH═CH₂,—O[Si(R)₂O]_(m)—(CH₂)_(p)—C≡CH,—O[Si(R)₂O]_(m)—[CH₂—C(CH₃)₂]_(q)—(CH₂)_(p)—C≡CH or—O[Si(R)₂O]_(m)—[CH₂₋C(CH₃)₂]_(q)—(CH₂)_(p)CH═CH₂ where n ranges from 2to 100, p ranges from 1 to 10 and q ranges from 2 to 25, or where X is—OC(═O)C(H)═CH₂, —OC(═O)C(CH₃)═CH₂, or —OC(═O)OCH₂(CH₂)_(p)CH═CH₂,wherein p ranges from 1 to 10, the crosslinking reaction may be carriedout either in the presence or in the absence of a crosslinking agent,for instance, a UV initiator (e.g., benzophenone, benzoyl peroxide,AIBN, etc.), a thermal initiator (e.g., a peroxide such as dicumylperoxide), or an organometallic catalyst (e.g., a platinum catalyst).The crosslinking reaction may be carried out using heat or usingradiation (e.g., UV-Visible light, electron beam, gamma beam, laserirradiation, etc.), moisture or a metal catalyst, either at roomtemperature or elevated temperature.

Example 3

Procedures such as are described above in Examples 1 and 2 can beemployed using a suitable polyisobutylene urethane, urea orurethane/urea copolymer (PIBPU) having a number average molecular weightranging from 100 to 100,000 Daltons with terminal functional groups, forinstance,

where n is an integer ranging from 1 to 50, and X is selected, forexample, from —CH═CH₂, —(CH₂)_(p)CH═CH₂ where p ranges from 1 to 10,—CH≡CH, —O[Si(R)₂O]_(m)CH═CH₂ where m ranges from 1 to 100 and R islower alkyl (e.g., —CH₃, —C₂H₅, etc.), —OC(═O)C(H)═CH₂ or—OC(═O)C(CH₃)═CH₂, or —O[Si(R)₂O]_(m)—(CH₂)_(p)—CH═CH₂,—O[Si(R)₂O]_(m)—(CH₂)_(p)—C≡CH,—O[Si(R)₂O]_(m)—[CH₂₋C(CH₃)₂]_(q)—(CH₂)_(p)—C≡CH or—O[Si(R)₂O]_(m)—[CH₂C(CH₃)₂]_(q)—(CH₂)_(p)CH═CH₂ where m ranges from 2to 100, ranges from 1 to 10 and q ranges from 2 to 25.

The crosslinking reaction may be carried out either in the presence orin the absence of a crosslinking agent, for instance, a UV initiator(e.g., benzophenone, benzoyl peroxide, AIBN, etc.), a thermal initiator(e.g., a peroxide such as dicumyl peroxide), or an organometalliccatalyst (e.g., a platinum catalyst). The crosslinking reaction may becarried out using heat or using radiation (e.g., UV-Visible light,electron beam, gamma beam, laser irradiation, etc.), moisture or a metalcatalyst, either at room temperature or elevated temperature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

The invention claimed is:
 1. A crosslinkable composition comprising (a) a polymer comprising a polyisobutylene segment and two or more unsaturated reactive groups, wherein the polymer is a urethane, urea, or urethane/urea copolymer, and (b) a free radical initiator.
 2. The crosslinkable composition of claim 1, wherein the polymer is a low molecular weight copolymer having a number average molecular weight ranging from 1,000 to 150,000 Daltons.
 3. The crosslinkable composition of claim 1, wherein the polymer comprises terminal groups selected from —CH═CH₂ and —CH≡CH.
 4. The crosslinkable composition of claim 1, wherein the polymer comprises terminal groups are selected from −O—[Si(R)₂O]_(m)—(CH₂)_(p)—CH═CH₂, where R is C1-C4 alkyl, m ranges from 1 to 100 and p ranges from 1 to
 10. 5. The crosslinkable composition of claim 1, wherein the free radical initiator is a free radical thermal initiator or photoinitiator.
 6. The crosslinkable composition of claim 1, wherein said composition is an adhesive that is cured by exposure to radiation, heat, an organometallic catalyst, a crosslinking agent, or a combination of the foregoing.
 7. The crosslinkable composition of claim 1, wherein the composition further comprises a crosslinking agent with multiple unsaturated groups.
 8. The crosslinkable composition of claim 1, wherein the composition further comprises a therapeutic agent.
 9. The crosslinkable composition of claim 1, wherein said polymer further comprises a non-polyisobutylene polymer segment.
 10. The crosslinkable composition of claim 9, wherein the non-polyisobutylene polymer segment is selected from a polyether segment, a fluorinated polyether segment, a fluoropolymer segment, a polyester segment, a polyacrylate segment, a polymethacrylate segment, a polysiloxane segment, a fluorinated polysiloxane, and a polycarbonate segment.
 11. The crosslinkable composition of claim 9, wherein the non-polyisobutylene polymer segment is selected from a polytetramethylene oxide segment, a polyhexamethylene oxide segment, a polydimethylsiloxane segment, a polyperfluoroalkylene oxide segment and a polyhexamethylene carbonate segment.
 12. The crosslinkable composition of claim 1, wherein the copolymer comprises a residue of an aromatic diisocyanate.
 13. The crosslinkable composition of claim 1, wherein the copolymer comprises a chain extender residue.
 14. A method of forming a medical device comprising crosslinking a crosslinkable composition in accordance with claim
 1. 15. The method of claim 14, wherein said crosslinking step is performed in conjunction with a step in which a coating is applied to a medical device component and crosslinked or in which an adhesive is crosslinked to adhere two or more medical device components to one another.
 16. The method of claim 14, wherein said medical device component or components comprise a copolymer that comprises a polyisobutylene segment.
 17. The method of claim 14, where said crosslinking step is performed in conjunction with an injection molding or extrusion operation.
 18. A method of forming a medical device comprising crosslinking a crosslinkable composition in accordance with claim 1 on a surface of a polymeric component that comprises a polyisobutylene segment.
 19. The method of claim 18, wherein said crosslinking step is performed in conjunction with a step in which a coating or adhesive layer is applied said medical device component.
 20. The method of claim 18, wherein said medical device component comprises a urethane, urea or urethane/urea copolymer that comprises a polyisobutylene segment.
 21. The crosslinkable composition of claim 1, wherein said polymer comprises more than two reactive groups.
 22. The crosslinkable composition of claim 1, wherein the free radical initiator is a free radical thermal initiator.
 23. The crosslinkable composition of claim 1, wherein the free radical initiator is a free radical photoinitiator.
 24. The crosslinkable composition of claim 1, wherein the polymer is a low molecular weight copolymer having a number average molecular weight ranging from 1,000 to 50,000 Daltons.
 25. The crosslinkable composition of claim 1, wherein the polymer is a low molecular weight copolymer having a number average molecular weight ranging from 1,000 to 20,000 Daltons.
 26. The crosslinkable composition of claim 9, wherein the non-polyisobutylene polymer segment is a poly(vinyl aromatic) segment.
 27. The crosslinkable composition of claim 9, wherein the non-polyisobutylene polymer segment is a polystyrene segment.
 28. The crosslinkable composition of claim 9, wherein the non-polyisobutylene polymer segment is a polyether segment.
 29. The crosslinkable composition of claim 9, wherein the composition further comprises a crosslinking agent with multiple unsaturated groups.
 30. The crosslinkable composition of claim 7, wherein the crosslinking agent comprises a terminally unsaturated polyether segment. 